PROJECT SUMMARY: E-cigarette aerosol contains reactive aldehydes including acetaldehyde, formaldehyde, and acrolein which are highly diffusible into cells. These reactive aldehydes, also found in tobacco cigarettes and alcohol, are known to cause cellular damage that can lead to cardiovascular disease. Further, ~560 million people in the world carry an aldehyde dehydrogenase 2 (ALDH2) genetic variant, ALDH2*2, that severely limits the metabolism of reactive aldehydes such as those present in e-cigarette aerosol. Having an ALDH2*2 variant increases the risk for cardiovascular disease, including cellular damage from a heart attack. However, little is known how the reactive aldehyde levels in e-cigarette aerosol, coupled with this genetic difference present in reactive aldehyde metabolism, effect cardiovascular physiology and cellular function. Here, we will study the effects on the cardiovascular system of e-cigarette aerosol in addition to the individual reactive aldehydes within e-cigarette aerosol using wild type ALDH2 or ALDH2*2 variant knock-in mice. We will do so by (AIM 1) exposing wild type ALDH2 mice and ALDH2*2 knock-in mice to e-cigarette aerosol while monitoring the heart by remote telemetry and quantifying in the heart and lungs the biochemical effects of e- cigarette aerosol exposure. In isolated adult cardiac myocytes (AIM 2), we will determine in wild type ALDH2 and ALDH2*2 knock-in mice how the individual reactive aldehydes in e-cigarette aerosol alter cellular protein adduct formation and cellular function. We will also determine how reactive aldehydes at the levels present in e-cigarette aerosol affect cardiac myocytes subjected to hypoxia-reoxygenation injury. In human umbilical vein endothelial cells and isolated lung primary endothelial cells (AIM3), we will also determine how reactive aldehyde exposure causes changes in protein adduct formation and mitochondrial function that leads to endothelial cell dysfunction. My research team can bring specific skill-sets and unique tools to this field. We will perform studies to uncover how e-cigarette aerosol and the reactive aldehyde present within the aerosol effect the cardiovascular system. In particular, these studies will address the cardiovascular effects of exposure to e-cigarette aerosol and investigate the effects of e-cigarette aerosol exposure on cardiac myocytes and endothelial cells.